Pyrimidine carboxamide compound and use thereof

Abstract

A pyrimidine carboxamide compound as shown in formula I, or a tautomer, mesomer, racemate, enantiomer and diastereomer thereof, or a mixture form thereof, or a pharmaceutically acceptable salt thereof, which can be used as a Vanin enzyme inhibitor, and can be used to prepare a medicament for treating various conditions, including Crohn's disease and ulcerative colitis.

1 . A pyrimidine carboxamide compound represented by formula I, or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or a mixture form thereof, or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
         wherein, R a1 , R a3  and R a5  are independently H, halogen, CN, C 1 -C 6  alkyl, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b ; 
         R a2  and R a4  are independently H, halogen; 
         R 4  and R 5  are independently H, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted by one or more than one halogen; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded; 
         R 6  and R 7  are independently H, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted by one or more than one R 1c , —N(R 2a R 2b ) or —N(R 3a )—(C═O)—R 3b ; 
         alternatively, R 6  and R 7  form a ring B together with the carbon to which they are bonded; 
         the ring B is 4- to 7-membered cycloalkyl, 4- to 7-membered heterocycloalkyl, 4- to 7-membered cycloalkyl substituted by one or more than one R 1d , or 4- to 7-membered heterocycloalkyl substituted by one or more than one R 1c ; the heteroatom of the 4- to 7-membered heterocycloalkyl in the 4- to 7-membered heterocycloalkyl and the 4- to 7-membered heterocycloalkyl substituted by one or more than one R 1e  is N, O or S, and the number of heteroatom is 1 or 2; 
         R 1a , R 1b , R 1c , R 1d  and R 1e  are independently halogen, C 1 -C 4  alkyl or C 1 -C 4  alkyl substituted by one or more than one halogen; 
         R 2a , R 2b , R 3a  and R 3b  are independently H or C 1 -C 4  alkyl. 
       
     
     
         2 . The pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein,
 R a1 , R a3  and R a5  are independently H, halogen, CN, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b ;   or,   
       
         
           
           
               
               
           
         
         or, R 1a  and R 1b  are independently halogen; 
         or, the number of R 1a  and R 1b  is 1, 2, 3, 4 or 5; 
         or, 
       
       
         
           
           
               
               
           
         
       
       R 4  and R 5  are independently C 1 -C 6  alkyl; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;
 or, R 6  and R 7  are independently H, N(R 2a R 2b ) or —N(R 3a )—(C═O)—R 3b ; alternatively, R 6  and R 7  form the ring B together with the carbon to which they are bonded; 
 or, the ring B is 4- to 7-membered heterocycloalkyl; 
 or, R 2a  and R 2b  are independently C 1 -C 4  alkyl; 
 or, R 3a  and R 3b  are independently C 1 -C 4  alkyl. 
 
     
     
         3 . The pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 2 , wherein,
 R a1 , R a3  and R a5  are independently H, halogen, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b ;   or,   
       
         
           
           
               
               
           
         
         or, the number of R 1a  and R 1b  is 2 or 3; 
         or, 
       
       
         
           
           
               
               
           
         
       
       R 4  and R 5  are independently C 1 -C 6  alkyl; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;
 or, R 6  and R 7  form the ring B together with the carbon to which they are bonded; 
 or, when R a1 , R a2 , R a3 , R a4  and R a5  are independently halogen, the halogen is fluorine, chlorine or bromine; 
 or, when R a1 , R a3  and R a5  are independently C 1 -C 6  alkyl, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b , the C 1 -C 6  alkyl in the C 1 -C 6  alkyl, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a  and C 1 -C 6  alkyl-O— substituted by one or more than one R 1b  is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tent-butyl; 
 or, when R 4  and R 5  are independently C 1 -C 6  alkyl, or C 1 -C 6  alkyl substituted by one or more than one halogen, the C 1 -C 6  alkyl in the C 1 -C 6  alkyl and the C 1 -C 6  alkyl substituted by one or more than one halogen is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tent-butyl; 
 or, when R 4  and R 5  are independently C 1 -C 6  alkyl substituted by one or more than one halogen, the halogen is fluorine, chlorine or bromine; 
 or, when R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded, the 3- to 7-membered cycloalkyl is independently cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; 
 or, when R 6  and R 7  are independently halogen, the halogen is fluorine, chlorine or bromine; 
 or, when R 6  and R 7  are independently C 1 -C 6  alkyl, or C 1 -C 6  alkyl substituted by one or more than one R 1c , the C 1 -C 6  alkyl in the C 1 -C 6  alkyl and the C 1 -C 6  alkyl substituted by one or more than one R 1c  is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tent-butyl; 
 or, when the ring B is 4- to 7-membered cycloalkyl, or 4- to 7-membered cycloalkyl substituted by one or more than one R 1d , the 4- to 7-membered cycloalkyl in the 4- to 7-membered cycloalkyl and the 4- to 7-membered cycloalkyl substituted by one or more than one R 1d  is independently cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; 
 or and when the ring B is 4- to 7-membered heterocycloalkyl, or 4- to 7-membered heterocycloalkyl substituted by one or more than one R 1e , the heteroatom of the 4- to 7-membered heterocycloalkyl in the 4- to 7-membered heterocycloalkyl and the 4- to 7-membered heterocycloalkyl substituted by one or more than one R 1e  is N or O, and the number of the heteroatom is 1; 
 or, when R 1a , R 1b , R 1c , R 1d  and R 1e  are independently halogen, or C 1 -C 4  alkyl substituted by one or more than one halogen, the halogen in the halogen and the C 1 -C 4  alkyl substituted by one or more than one halogen is independently fluorine, chlorine or bromine; 
 or, when R 1a , R 1b , R 1c , R 1d  and R 1e  are independently C 1 -C 4  alkyl, or C 1 -C 4  alkyl substituted by one or more than one halogen, the C 1 -C 4  alkyl in the C 1 -C 4  alkyl and the C 1 -C 4  alkyl substituted by one or more than one halogen is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tent-butyl; 
 or, when R 2a , R 2b , R 3a  and R 3b  are independently C 1 -C 4  alkyl, the C 1 -C 4  alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tent-butyl. 
 
     
     
         4 . The pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 3 , wherein,
 R a1 , R a3  and R a5  are independently H, halogen, or C 1 -C 6  alkyl substituted by one or more than one R 1a ;   or, when R a1 , R a2 , R a3 , R a4  and R a5  are independently halogen, the halogen is fluorine or chlorine;   or, when R a1 , R a3  and R a5  are independently C 1 -C 6  alkyl, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b , the C 1 -C 6  alkyl in the C 1 -C 6  alkyl, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a  and C 1 -C 6  alkyl-O— substituted by one or more than one R 1b  is independently methyl or isopropyl;   or, when R 4  and R 5  are independently C 1 -C 6  alkyl, C 1 -C 6  alkyl substituted by one or more than one halogen, the C 1 -C 6  alkyl in the C 1 -C 6  alkyl and the C 1 -C 6  alkyl substituted by one or more than one halogen is independently methyl;   or, when R 4  and R 5  are independently C 1 -C 6  alkyl substituted by one or more than one halogen, the halogen is fluorine or chlorine;   or, when R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded, the 3- to 7-membered cycloalkyl is independently cyclopropyl;   or,   
       
         
           
           
               
               
           
         
       
       R 4  and R 5  are independently C 1 -C 6  alkyl; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;
 or, R 6  and R 7  form the ring B together with the carbon to which they are bonded; the ring B is 4- to 7-membered heterocycloalkyl; 
 or, when the ring B is 4- to 7-membered heterocycloalkyl, or 4- to 7-membered heterocycloalkyl substituted by one or more than one R 1e , the 4- to 7-membered heterocycloalkyl in the 4- to 7-membered heterocycloalkyl and the 4- to 7-membered heterocycloalkyl substituted by one or more than one R 1e  is tetrahydropyranyl; 
 or, when R 1a , R 1b , R 1c , R 1d  and R 1e  are independently halogen, or C 1 -C 4  alkyl substituted by one or more than one halogen, the halogen in the halogen and the C 1 -C 4  alkyl substituted by one or more than one halogen is independently fluorine or chlorine; 
 or, when R 1a , R 1b , R 1c , R 1d  and R 1e  are independently C 1 -C 4  alkyl, or C 1 -C 4  alkyl substituted by one or more than one halogen, the C 1 -C 4  alkyl in the C 1 -C 4  alkyl and the C 1 -C 4  alkyl substituted by one or more than one halogen is independently methyl; 
 or, when R a1 , R a3  and R a5  are independently C 1 -C 6  alkyl substituted by one or more than one R 1a  or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b , the R a1 , R a3  and R a5  are independently trifluoromethyl, trifluoromethyl-O—; 
 or, when R 2a , R 2b , R 3a  and R 3b  are independently C 1 -C 4  alkyl, the C 1 -C 4  alkyl is independently methyl. 
 
     
     
         5 . The pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein, the pyrimidine carboxamide compound represented by formula I is adapted to scheme 1, scheme 2, scheme 3, scheme 4;
 scheme 1:   R a1 , R a3  and R a5  are independently H, halogen, CN, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b ;   R a2  and R a4  are independently H, halogen;   R 4  and R 5  are independently H, C 1 -C 6  alkyl; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;   R 6  and R 7  are independently H, —N(R 2a R 2b ) or —N(R 3a )—(C═O)—R 3b ;   alternatively, R 6  and R 7  form the ring B together with the carbon to which they are bonded;   the ring B is 4- to 7-membered heterocycloalkyl;   R 1a  is independently halogen;   R 2a , R 2b , R 3a  and R 3b  are independently H or C 1 -C 4  alkyl;   scheme 2:   R a1 , R a3  and R a5  are independently H, halogen, CN, C 1 -C 6  alkyl-O—, C 1 -C 6  alkyl substituted by one or more than one R 1a , or C 1 -C 6  alkyl-O— substituted by one or more than one R 1b ;   R a2  and R a4  are independently H, halogen;   R 4  and R 5  are independently H, C 1 -C 6  alkyl; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;   R 6  and R 7  form the ring B together with the carbon to which they are bonded; the ring B is 4- to 7-membered heterocycloalkyl;   R 1a  is independently halogen;   scheme 3:   R a1 , R a2 , R a3 , R a4  and R a5  are independently H or halogen;   
       
         
           
           
               
               
           
         
       
       R 4  and R 5  are independently C 1 -C 6  alkyl; alternatively, R 4  and R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;
 R 6  and R 7  form the ring B together with the carbon to which they are bonded; the ring B is 4- to 7-membered heterocycloalkyl; 
 scheme 4: 
 R a1 , R a2 , R a3 , R a4  and R a5  are independently H or halogen; 
 
       
         
           
           
               
               
           
         
       
       R 4  and R 5  are independently C 1 -C 6  alkyl; alternatively, Rand R 5  form 3- to 7-membered cycloalkyl together with the carbon to which they are bonded;
 R 6  and R 7  form the ring B together with the carbon to which they are bonded; the ring B is 4- to 7-membered heterocycloalkyl. 
 
     
     
         7 . The pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein,
 the pyrimidine carboxamide compound represented by formula I is selected from any one of the following structures:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition, comprising the pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutical excipient. 
     
     
         9 . A method for inhibiting Vanin-1 in a subject in need thereof, comprising: administering the pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1  to the subject. 
     
     
         10 . A method for preventing and/or treating diseases related to Vanin-1 in a subject in need thereof, comprising: administering the pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1  to the subject. 
     
     
         11 . The method according to  claim 10 , wherein the diseases related to Vanin-1 are one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases. 
     
     
         12 . The method according to  claim 11 , wherein one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases are selected from Crohn's disease, ulcerative colitis, inflammatory bowel disease and gastritis. 
     
     
         13 . A method for preventing and/or treating one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases in a subject in need thereof, comprising: administering the pyrimidine carboxamide compound represented by formula I, or the tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or the mixture form thereof, or the pharmaceutically acceptable salt thereof according to  claim 1  to the subject. 
     
     
         14 . The method according to  claim 13 , wherein one or more of autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infection-based diseases, fibrotic diseases, cardiovascular diseases, respiratory diseases, renal diseases, dermatological diseases, liver diseases, gastrointestinal diseases, oral diseases and hematopoietic diseases are selected from Crohn's disease, ulcerative colitis, inflammatory bowel disease and gastritis.